DE3912100A1 - SUBSTITUTED URACILES, PROCESS FOR THEIR PREPARATION AND USE AGAINST PARASITOUS PROTOZOES - Google Patents

Description

The present invention relates to new substituted ones Uracile, process for their preparation, intermediates to carry out these methods and their Use against parasitic protozoa.

The use of F-substituted uracil to combat of coccidia is known. The effect of this Connection does not satisfy in any case (US-P 30 17 322).

The present invention relates

• 1. Novel substituted uracils of the general formula (I) in which
  R¹ represents aromatic or heteroaromatic radicals which are optionally substituted,
  R 2 is H, alkyl, alkenyl, alkynyl or aralkyl which are optionally substituted,
  R³ is one or more, identical or different radicals of the group hydrogen, halogen, alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, haloalkylthio, cyano, alkoxycarbonyl, alkylsulfonyl, haloalkylsulfonyl,
  R⁴ is hydrogen, a straight-chain, branched or cyclic alkyl radical, alkenyl, alkynyl or aralkyl, which are optionally substituted.
• 2. Process for the preparation of substituted uracils of the general formula (Ia) in which
  R¹ represents aromatic or heteroaromatic radicals which are optionally substituted,
  R² is hydrogen, alkyl, alkenyl, alkynyl or aralkyl, which are optionally substituted,
  R³ is one or more, identical or different radicals of the group hydrogen, halogen, alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, haloalkylthio, cyano, alkoxycarbonyl, alkylsulfonyl, haloalkylsulfonyl,
  R⁴ is hydrogen, a straight-chain, branched or cyclic alkyl radical, alkenyl, alkynyl or aralkyl, which are optionally substituted,
  by
  • a) compounds of the formula (II) in which
    R¹, R², R³ and R⁴ have the meanings given above, and
    Alk is C₁-C₄-alkyl, in particular ethyl,
• optionally heated in the presence of bases, or by
  • b) Compounds of the formula (Ia) in which R¹, R², R³ and R⁴ have the meanings given above,
    with compounds of the formula (III) R⁴-A in which
    R⁴ is optionally substituted alkyl, alkenyl, alkynyl or aralkyl and
    A represents halogen, -OSO₂-alkyl, -OSO₂-aryl, -OSO₂-haloalkyl,
• or by putting
  • c) Compounds of the formula (IV) in which
    R¹, R², R³ have the meanings given above,
    decarboxylated by heating.
• 3. Novel compounds of the formula (II) in which
  R¹, R², R³ and R⁴, Alk have the meanings given in method 2a).
• 4. A process for the preparation of the compounds of formula (II) according to 3, characterized in that
  • a) compounds of the formula (V) in which
    R¹, R², R³ have the abovementioned meanings,
    with isocyanates of the formula (VI) in which
    Alk has the abovementioned meaning,
    implements, or
  • b) compounds of the formula (VII) in which R¹, R², R³ have the abovementioned meanings,
    with compounds of the formula (VIII) in which
    R⁴ or Alk has the abovementioned meanings, is reacted.
• 5. Novel compounds of the formula (IV) in which
  R¹, R², R³, R⁴ have the meanings given above.
• 6. A process for preparing the novel compounds of the formula (IV) according to 5, characterized in that compounds of the formula (IX) in which
  R¹, R², R³ and R⁴ have the meanings given above,
  heated in the presence of aqueous acids.
• 7. Novel compounds of the formula (IX) in which
  R¹, R², R³, R⁴ have the meanings given above.
• 8. Process for the preparation of the novel compounds of the formula (IX) according to 7, characterized in that compounds of the formula (X) in which
  R¹, R², R³, R⁴, Alk have the abovementioned meaning,
  heated in the presence of bases.
• 9. Novel compounds of the formula (X) in which
  R¹, R², R³, R⁴ and Alk have the meanings described under 4b).
• 10. A process for the preparation of the novel compounds of the formula (X) according to 9, which comprises reacting compounds of the formula (V) in which
  R¹, R², R³ have the meanings described under 4b),
  with compounds of the formula (XI) in which
  Alk is the same or different C₁-C₄-alkyl,
  implements.

The compounds of the formula (I) and their salts with Acids or bases are excellent for controlling parasitic protozoa suitable.

Preferred compounds of the formula (I) are compounds in which
R¹ is thiazolyl optionally substituted by halogen, alkyl, cyano, alkoxy, alkylthio, methylenedioxy, ethylenedioxy, alkylsulfinyl, alkylsulfonyl, haloalkyl, haloalkoxy, haloalkylthio, haloalkylsulfinyl, haloalkylsulfonyl, oxazolyl, benzthiazolyl, benzoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzimidazolyl, Phenyl or naphthyl,
R² is H or alkyl,
R³ is one or more, identical or different radicals from the group halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio or cyano,
R⁴ is hydrogen, alkyl, alkenyl or alkynyl, which are optionally substituted by halogen, haloalkyl, alkoxy, alkylthio, aryloxy, arylthio or aryl.

Particular preference is given to compounds of the formula (I) in which
R¹ is phenyl, pyridyl, benzthiazolyl which is substituted by one or more identical or different radicals of the group halogen, C _1-4 -alkyl, C _1-4 -haloalkyl, C _1-4 -alkoxy, C _1-4 -alkylthio, C _1-4 haloalkoxy, C _1-4 haloalkylthio, cyano, C _1-4 alkoxycarbonyl, C _1-4 alkylsulfinyl, C _1-4 alkylsulfonyl, C _1-4 haloalkylsulfinyl, C _1-4 haloalkylsulfonyl is substituted,
R 2 is H or C _1-4 -alkyl,
R³ is one or more, identical or different radicals of the group hydrogen, halogen, C _1-4 -alkyl, C _1-4 -haloalkyl,
R⁴ is hydrogen.

Very particular preference is given to compounds of the formula (I) in which
R¹ is phenyl which is optionally substituted by halogen, in particular chlorine, bromine, fluorine, C _1-4 -haloalkyl, in particular trifluoromethyl, C _1-4 -haloalkylthio, in particular trifluoromethylthio, C _1-4 -haloalkoxy, in particular trifluoromethoxy, C _{1 4-} alkyl, in particular methyl, C _1-4 -haloalkylsulfinyl, such as trifluoromethylsulfinyl, C _1-4 -haloalkylsulfonyl, such as trifluoromethylsulfonyl,
R 2 is H or C _1-4 -alkyl, in particular methyl,
R³ is halogen, in particular bromine, chlorine, fluorine, C _1-4 -alkyl, in particular methyl, haloalkyl, in particular trifluoromethyl,
R⁴ is hydrogen.

As individual compounds may be mentioned:

Furthermore, the following compounds may be mentioned:

In method 2) as the compound of formula (II) is 2,6-dichloro-α - (4'-chlorophenyl) -4- (3-ethoxyacryloyl) - used ureido-phenylautonitril, the process can be described by the following scheme:

The compounds of formula (II) are new. They are after the method described under 4.

Preference is given to compounds of the formula (II), in the R¹, R², R³ in the compounds of the formula (I) have preferred meanings mentioned.

Specifically, the following compounds of the formula (II) called.

The process 2a) is carried out by using a Compound of the formula (II) in bulk or in solution, optionally heated in the form of its salt. To completed reaction, the reaction mixture with acidified in dilute inorganic acid (eg hydrochloric acid) and the precipitated solid filtered off.

Virtually all diluents are used inert organic solvents in question. For this preferably include aliphatic and aromatic, optionally halogenated hydrocarbons, gasoline,  Ligroin, benzene, toluene, xylene, methylene chloride, ethylene chloride, Carbon tetrachloride, chlorobenzene and o-dichlorobenzene, ethers such as diethyl and dibutyl ether, Glycol dimethyl ether and diglycol dimethyl ether, tetrahydrofuran and dioxane, ketones such as acetone, methyl, Ethyl, methyl isopropyl and methyl isobutyl ketone, Esters such as methyl acetate and ethyl acetate, nitriles such as For example, acetonitrile and propionitrile, amides such as. B. Dimethylformamide, dimethylacetamide and N-methyl-pyrrolidone and dimethyl sulfoxide, tetramethylene sulfone and Hexamethylphosphoric triamide, alcohols such as ethanol or tert. Butanol.

The reaction is carried out in the presence of inorganic or carried out organic bases.

As such may be mentioned z. B .:
Alkali metal hydroxides such as. For example, sodium and potassium hydroxide, alkaline earth metal hydroxides such. As calcium hydroxide, alkali metal acetates such as sodium acetate, alkali metal carbonates and alcoholates such as sodium and potassium carbonate, sodium and potassium or ethylate or potassium tert. Butylate, further aliphatic, aromatic or heterocyclic amines, for example triethylamine, pyridine, 1,5-diazabicyclo [4,3,0] non-5-ene (DBN), 1,8-diazabicyclo [5,4,0 ] -undec-7-ene (DBU) and 1,4-diazabicyclo [2,2,2] octane (DABCO).

The reaction takes place at temperatures between 80 ° C and 200 ° C, preferably between 80 ° C and 160 ° C, at atmospheric pressure or increased pressure. It is preferred at atmospheric pressure worked.

If, in the process 2b) as compounds of formula (Ia) 2,6-dichloro-α - (2 ', 4'-dichlorophenyl) - a-methyl-4- (1-uracil) -phenylacetonitrile and the compound of formula (III) methyl iodide, the process can be described by the following formula scheme:

The compounds of formula (Ia) are new and will be like described in method 2a).

The compounds of the formula (IV) are known or can be represented by known methods. Especially mentioned is methyl iodide, ethyl bromide.

The process is performed by connecting of the formula (Ia) in the presence of a base and a Diluent with compounds of the formula (IV) implements. As a diluent, all inert  organic solvents are used, too to carry out processes (2a).

The process is carried out in the presence of bases. As preferred bases may be mentioned, the alkali metal hydroxides such as sodium hydroxide, alkali metal alcoholates such as sodium methylate or potassium butoxide, metal hydrides such as sodium hydride or organic bases such as 1,8-diazabicyclo [5] - undec-7-en (DBU).

The process is carried out at normal pressure and Temperatures between 20 ° C and 140 ° C.

The reaction is carried out by equimolar Combining amounts of the compound of the formula (Ia) and base, this mixture with an equimolar amount of Compound of formula (IV) is added and the reaction temperature heated.

If, in the procedure 2c) for preparing the compounds (I) as the compound of formula (IV) 2,6-dichloro-a - (2 ', 6'-dichlorophenyl) -4- (5-carboxy-1-uracil) - Phenylacetonitrile, the process can be described by the following equation:

The compounds of formula (IV) are new. Your production takes place after that described under (6) Method.

Preference is given to using compounds of the formula (IV) in the R¹, R², R³ in the compounds of the Formula (I) mentioned preferred and particularly preferred Has meanings.

The decarboxylation is carried out by heating in the presence mercapto-containing carboxylic acids such. B. Mercaptoacetic acid or thiosalicylic acid, optionally in the presence of inert organic diluents carried out. Diluents include aliphatic and aromatic, optionally halogenated Hydrocarbons such as nonane, decane, dodecane, xylenes, Ethers, such as ethylene glycol monobutyl ether, diethylene glycol dibutyl ether.

The reaction takes place at temperatures between 150 ° C. and 300 ° C, preferably between 160 ° C and 250 ° C, in particular between 170 ° C and 210 ° C.

It is worked at atmospheric pressure. The connections of the Formula (IV) are used in substance or in the respective diluent, dissolved or suspended together with the mercapto-containing carboxylic acid heated.

Is used in process 4 for the preparation of the compounds of formula (II) as the compound of formula (V) is 2,6-dichloro- α - (4'-chlorophenyl) -4-aminophenylacetonitrile and used as the compound of formula (VI) ethoxyaryloyl isocyanate the method is described by the following scheme:

The compounds of formula (V) are known in part (US-P 40 005 218) or can according to the described there Process are produced. Partly they are the subject a not yet published application of Applicant (DE-OS 38 34 272.3)

Preference is given to compounds of the formula (V), in R¹, R², R³ in the case of the compounds of the formula (I) mentioned, preferred or particularly preferred meanings have. In particular, the compounds of the called the following formula:

The compounds of the formula (VI) are known.

The reaction is preferably carried out using diluents carried out.

The diluent is virtually all inert organic solvents in question. These include preferably aliphatic and aromatic, optionally halogenated hydrocarbons, gasoline, ligroin, Benzene, toluene, xylene, methylene chloride, ethylene chloride, Chloroform, carbon tetrachloride, chlorobenzene and o-dichlorobenzene, Ethers, such as diethyl and dibutyl ether, glycol dimethyl ether and diglycol dimethyl ether, tetrahydrofuran and dioxane, ketones such as acetone, methyl-ethyl, methyl-isopropyl and methyl isobutyl ketone, esters like  Methyl acetate and ethyl acetate, nitriles such as z. For example, acetonitrile and propionitrile, dimethylacetamide and N-methyl-pyrrolidone and dimethyl sulfoxide, tetramethylene sulfone and hexamethylphosphoric triamide.

The reaction takes place at temperatures between 20 ° C and 180 ° C, preferably between 30 ° C and 50 ° C.

The procedure is carried out by approximately equimolar Amounts of the compounds of the formula (V) and (VI) in combined one of the specified diluents and heated. After completion of the implementation will cooled and the precipitated solid filtered off, washed and dried.

If, in the process 4b) for the preparation of compounds of formula (II) as a compound of formula (VII) 4-isocyanato-2,6-dichloro- α - (4-chlorophenyl) - α - methyl-phenylacetonitrile and the compound of the formula (VIII) ethoxyacryloyl-N-methylamide, the process can be described by the following formula scheme:

As individual compounds of the formula (VII), mention may be made:

The procedure is carried out by about equimolar Amounts of the compound of formula (VII) and compound of the formula (VIII), if appropriate in the presence a diluent and a base. When Diluents find in the preparation of the Compounds (I) listed solvents use. Additionally mentioned is pyridine. As bases find the Method 2b described use. As particularly preferred be called sodium hydride.

The reaction takes place and normal or elevated pressure at temperatures between 20 ° C and 150 ° C, preferably between 30 ° C and 80 ° C.  

The compounds are preferably in equimolar proportions used and after completed Reaction filtered off as a solid product.

In method 6) for preparing the compound (IV) as the compound of formula (IX) 2,6-dichloro-α - (4'-methylphenyl) -4- (5-cyano-1-uracil) phenylacetonitrile used, can be describe the process by the following scheme:

The compounds of formula (IX) are new. Your production takes place according to the procedure described under 8). In detail, the following compounds of Called formula (IX):

The hydrolysis is carried out under acidic conditions. The acids used are mineral acids, such as z. Hydrochloric, hydrobromic, sulfuric and Mixtures of mineral acids and organic acids, such as z. As acetic acid or propionic acid.

The reaction takes place at temperatures between 80 ° C and 120 ° C. It is worked under normal pressure.

The compounds of the formula (IX) are 10 to 30 times Volume of acid or acid mixture dissolved and heated until complete hydrolysis.  

In a variant, starting from the compounds of the formula (IX) directly the compounds of the formula (I) to be obtained. This is achieved by adding at Method 2c) described mercaptogruppenhaltigen Carboxylic acids, preferably mercaptoacetic acid for Hydrolysis.

In method 8) for preparing the compounds (IX) (the compound of formula X) of 2,6-dichloro- α - (4'-methylphenyl) -4-N- (2-cyano-acryloylurethan) used amino-phenylacetonitrile, can the process be described by the following scheme:

The compounds of formula X are new. Preferred are the compounds of the formula X in which R¹, R², R³ in the compounds of formula I mentioned have preferred meanings.

Specifically, the following compounds of the formula X called:

The process is performed by connecting of the formula (X), if appropriate in the presence a solvent and a base.

As solvents and bases found in the production the solvents listed in the compounds (I) Use. As a particularly preferred organic Solvents are alcohols such. For example, ethanol or organic acids such. B. glacial acetic acid used.

Particularly preferred bases are the hydroxides and Acetates of alkali or alkaline earth metals such. B. NaOH or sodium and potassium acetate.  

The reaction is carried out under atmospheric pressure at temperatures between 70 ° C and 150 ° C, preferably between 70 ° C and 100 ° C.

The base used is in 10 to 80% molar Excess used. The reaction mixture is after completed cyclization preferably with a diluted mineral acid such. Hydrochloric acid is acidified and the product obtained as a solid filtered off.

If in the process 10) for preparing the compounds (X) 2,6-dichloro- α - (4'-methylphenyl) -4- acetonitrile and (as the compound of formula XI) N- (2-cyano-3-ethoxyacryloyl) urethane used, the process can be described by the following scheme:

The procedure is carried out by making connections of the formula (V) with approximately equimolar amount of N- (2-cyano-3-) alkoxy-acryloyl) urethane in a diluent heated and the precipitated after cooling solid sucks.  

The solvents mentioned in process 2a) in question.

The reaction is between 50 ° C and 150 ° C, preferred between 80 ° C and 100 ° C, carried out.

The active ingredients are suitable for low toxicity to warm-blooded animals to combat parasitic protozoa and in animal husbandry and animal breeding at commercial, Breeding, zoo, laboratory, experimental and hobby animals occurrence. They are against all or individual Developmental stages of the pests and against resistant and normally sensitive strains are effective. By fighting the parasitic protozoa are said to be disease, Deaths and reductions in performance (eg in production of meat, milk, wool, skins, eggs, honey etc.) are reduced so that through the use of Active ingredients a more economical and easier animal husbandry is possible.

The parasitic protozoa include:
Mastigophora (flagellata) such. B. Trypanosomatidae z. B. Trypanosoma b. Brucei, T. b. gambiense, T. b. rhodesiense, T. congolense, T. cruzi, T. evansi, T. equinum, T. lewisi, T. percae, T. simiae, T. vivax, Leishmania brasiliensis, L. donovani, L. tropica, such as. B. Trichomonadidae z. G., Giardia lamblia, G. canis.

Sarcomastigophora (Rhizopoda) as Entamoebidae z. B. Entamoeba histolytica, Hartmanellidae z. Acanthamoeba sp., Hartmanella sp.  

Apicomplexa (Sporozoa) as Eimeridae z. B. Eimeria acervulina, E. adenoids, E. alabahmensis, E. anatis, E. anseris, E. arloingi, E. ashata, E. auburnensis, E. bovis, E. brunetti, E. canis, E. chinchillae, E. clupearum, E. columbae, E. contorta, E. crandalis, E. dabliecki, E. dispersa, E. elipsoidales, E. E. falciformis, E. faurei, E. flavescens, E. gallopavonis, E. hagani, E. intestinalis, E. iroquoina, E. irresidua, E. labbeana, E. leucarti, E. magna, E. maxima, E.media, E. meleagridis, E. meleagrimitis, E. mitis, E. necatrix, E. ninakohlyakimovae, E.ovis, E.parva, E.pavonis, E. perforans, E. phasani, E. piriformis, E. praecox, E. residua, E. scabra, E. spec., E. stiedai, E. suis, E. tenella, E. truncata, E. truttae, E. zuernii, Globidium spec., Isospora belli, I. canis, I. felis, I. ohioensis, I. rivolat, I. spec., I. suis, Cystisospora spec., Cryptosporidium spec. as Toxoplasmadidae z. B. Toxoplasma gondii, such as Sarcocystidae z. Sarcocystis bovicanis, S. bovihominis, S. ovicanis, S. ovifelis, S. spec., S. suihominis as Leucozoidae z. B. Leucozytozoon simondi, such as Plasmodiidae z. Plasmodium berghei, P. falciparum, P. malariae, P. ovale, P. vivax, P. spec., As Piroplasmea z. Babesia argentina, B. bovis, B. canis, B. spec., Theileria parva, Theileria spec., as Adeleina z. Heptazoon canis, H. spec.

Furthermore, Myxospora and Microspora z. Glugea spec. Nosema spec.  

Pneumocystis carinii, as well as Ciliophora (Ciliata) such as B. Balantidium coli, Ichthiophthirius spec., Trichodina spec., Epistylis spec.

In addition, the compounds of the invention effective against different to the helminths (Worms) counting fish parasites.

For the breeding and breeding animals include mammals such. B. Cattle, Horses, Sheep, Pigs, Goats, Camels, Water buffalo, Donkeys, rabbits, fallow deer, reindeer, fur animals such as As mink, chinchilla, raccoon, birds such. B. Chickens, geese, turkeys, ducks, pigeons, bird species for Home and zookeeping. It also includes utility and Ornamental fish.

Laboratory and experimental animals include mice, rats, Guinea pigs, golden hamsters, dogs and cats.

Hobby animals include dogs and cats.

The fish include commercial, breeding, aquarium and Ornamental fish of all ages in fresh and salt water Life. Among the useful and breeding fish count z. Carp, eel, trout, whitefish, salmon, bream, Roach, rudd, chub, sole, plaice, halibut, Japanese yellowtail (Seriola quinqueradiata), Japanaal (Anguilla japonica), Red seabream (Pagurus major), Seabass (Dicentrarchus labrax), Gray mullet (Mugilus cephalus), Pompano, Gilthread seabream (Sparus auratus), Tilapia spp., Chichliden species such. Plagioscione,  Channel catfish. Particularly suitable are the inventive Means for the treatment of fish fry, z. B. carp from 2-4 cm body length. Very well suited are the Medium also in the Eelmast.

The application can be both prophylactic and therapeutic respectively.

The application of the active ingredients takes place directly or in the form of suitable preparations enteral, parenteral, dermal, nasal.

The enteral application of the active ingredients happens z. B. orally in the form of powders, suppositories, tablets, capsules, Pastes, potions, granules, drenches, boluses, medicated Food or drinking water. The dermal application happens z. In the form of diving (dipping), spraying (spraying), Bathing, washing, pouring (on-pour and spot-on) and of powdering. The parenteral application happens z. B. in the form of injection (intramuscular, subcutaneous, intravenously, intraperitoneally) or by implants.

Suitable preparations are:

Solutions such as injectable solutions, oral solutions, concentrates for oral administration after dilution, solutions for use on the skin or in body cavities, infusion formulations, gels;
Emulsions and suspensions for oral or dermal use and for injection; Semi-solid preparations; Formulations in which the active substance is processed in an ointment base or in an oil in water or water in oil emulsion base;

Solid preparations such as powders, premixes or concentrates, Granules, pellets, tablets, boluses, capsules; Aerosols and inhalants, active substance-containing moldings.

Injection solutions are given intravenously, intramuscularly and administered subcutaneously.

Injection solutions are prepared by adding the active ingredient is dissolved in a suitable solvent and possibly additives such as solubilizers, acids, bases, Buffer salts, antioxidants, preservatives added become. The solutions are sterile filtered and bottled.

As solvents may be mentioned: Physiologically acceptable Solvents such as water, alcohols such as ethanol, Butanol, benzyl alcohol, glycerine, hydrocarbons, Propylene glycol, polyethylene glycols, N-methylpyrrolidone, and mixtures thereof.

The active ingredients can be optionally in physiological compatible with plant or synthetic Dissolve oils suitable for injection.

As solubilizers may be mentioned: solvents, the Promote the solution of the active ingredient in the main solvent  or prevent its failing. Examples are polyvinylpyrrolidone, polyoxyethylated castor oil, polyoxyethylated Sorbitan.

Preservatives are: benzyl alcohol, trichlorobutanol, p-hydroxybenzoic acid ester, n-butanol.

Oral solutions are applied directly. concentrates after previous dilution to the application concentration applied orally. Oral solutions and concentrates are described as above for the injection solutions produced, with no need for sterile work can be.

Solutions for use on the skin are dripped, brushed, rubbed, sprayed on, sprayed on or applied by dipping, bathing or washing. These solutions are as above for the injection solutions described prepared.

It may be beneficial in making thickeners inflict. Thickeners are: Inorganic Thickeners such as bentonites, colloidal Silica, aluminum monostearate, organic thickener such as cellulose derivatives, polyvinyl alcohols and their copolymers, acrylates and methacrylates.

Gels are applied to the skin or painted on or introduced into body cavities. Gels are made by using solutions like the injection solutions have been prepared described with so much  Thickeners are added that a clear mass with ointment-like consistency. As a thickener are the thickeners given above used.

Infusion formulations are limited to the areas of Skin infused or sprayed with the active ingredient either the skin penetrates and acts systemically or spread on the body surface.

Pour-on formulations are prepared by the Active substance in suitable skin-compatible solvents or solvent mixtures dissolved, suspended or is emulsified. Optionally, other auxiliaries such as dyes, absorption-promoting substances, Antioxidants, light stabilizers, adhesives added.

The following may be mentioned as solvents: water, alkanols, glycols, Polyethylene glycols, polypropylene glycols, glycerin, aromatic alcohols, such as benzyl alcohol, phenylethanol, Phenoxyethanol, esters such as ethyl acetate, butyl acetate, benzyl benzoate, Ethers, such as alkylene glycol alkyl ethers, such as dipropylene glycol monomethyl ether, Diethylene glycol mono-butyl ether, Ketones such as acetone, methyl ethyl ketone, aromatic and / or aliphatic hydrocarbons, vegetable or synthetic oils, DMF, dimethylacetamide, N-methylpyrrolidone, 2-dimethyl-4-oxy-methylene-1,3-dioxolane.

Dyes are all approved for animal use Dyes that may be dissolved or suspended.  

Absorption promoting substances are z. B. DMSO, spreading Oils such as isopropyl myristate, dipropylene glycol pelargonate, Silicone oils, fatty acid esters, triglycerides, fatty alcohols.

Antioxidants are sulfites or metabisulfites like Potassium metabisulfite, ascorbic acid, butylhydroxytoluene, Butylhydroxyanisole, tocopherol.

Light stabilizers are z. B. substances from the class of Benzophenone or novantisolic acid.

Adhesives are z. B. cellulose derivatives, starch derivatives, Polyacrylates, natural polymers such as alginates, gelatin.

Emulsions can be administered orally, dermally or as injections become.

Emulsions are either of the water-in-oil type or of the Type oil in water.

They are made by taking the active ingredient either in the hydrophobic or in the hydrophilic phase dissolves and these with the aid of suitable emulsifiers and optionally further auxiliaries, such as dyes, absorption promoting substances, preservatives, antioxidants, Light stabilizer, viscosity increasing Substances homogenized with the solvent of the other phase.  

As hydrophobic phase (oils) may be mentioned: paraffin oils, silicone oils, natural vegetable oils such as sesame oil, almond oil, castor oil, synthetic triglycerides such as caprylic / capric acid biglycerid, triglyceride mixture with vegetable fatty acids of chain length C _8-12 or other specially selected natural fatty acids, partial glyceride mixtures saturated or unsaturated fatty acids also possibly containing hydroxyl groups, mono- and diglycerides of the C₈ / C₁₀ fatty acids.

Fatty acid esters such as ethyl stearate, di-n-butyryl adipate, lauric acid hexyl ester, dipropylene glycol pelargonate, esters of a medium-chain branched fatty acid with saturated fatty alcohols of chain length C _16-18 , isopropyl myristate, isopropyl palmitate, caprylic / capric esters of saturated fatty alcohols of chain length C _12-18 , Isopropyl stearate, oleyl oleate, oleic acid ethyl ester, ethyl oleate, ethyl lactate, waxy fatty acid esters such as dibutyl phthalate, diisopropyl adipate, the latter related ester mixtures, inter alia fatty alcohols such as isotridecyl alcohol, 2-octyldodecanol, cetylstearyl alcohol, oleyl alcohol.

Fatty acids such. As oleic acid and its mixture.

As hydrophilic phase may be mentioned:
Water, alcohols such. As propylene glycol, glycerol, sorbitol and their mixtures.

As emulsifiers may be mentioned: nonionic surfactants, for. Polyoxyethylated castor oil, polyoxyethylated sorbitan monooleate, sorbitan monostearate, glycerol monostearate, polyoxyethyl stearate, alkylphenol polyglycol ethers;
ampholytic surfactants such as di-Na-N-lauryl- β -iminodipropionate or lecithin;
anionic surfactants, such as Na lauryl sulfate, fatty alcohol ether sulfates, mono / dialkyl polyglycol ether orthophosphoric acid monoethanolamine salts;
cationic surfactants such as cetyltrimethylammonium chloride.

Other auxiliaries which may be mentioned are: viscosity-increasing and the emulsion stabilizing substances such as Carboxymethylcellulose, methylcellulose and others Cellulose and starch derivatives, polyacrylates, alginates, Gelatin, gum arabic, polyvinylpyrrolidone, polyvinyl alcohol, Copolymers of methyl vinyl ether and Maleic anhydride, polyethylene glycols, waxes, colloidal silica or mixtures of the listed Substances.

Suspensions may be oral, dermal or as an injection be applied. They are manufactured by using the Active ingredient in a carrier liquid optionally with the addition of further auxiliaries, such as wetting agents, dyes, absorption promoting substances, preservatives, Antioxidants suspended light stabilizer.  

As carrier liquids are all homogeneous solvents and solvent mixtures called.

As wetting agents (dispersants) are the above mentioned surfactants mentioned.

As further auxiliaries are those specified above called.

Semi-solid preparations may be administered orally or dermally become. They are different from the ones described above Suspensions and emulsions only by their higher viscosity.

For the preparation of solid preparations, the active ingredient with suitable excipients, if appropriate with addition of excipients and into the desired shape brought.

Suitable carriers are all physiologically acceptable solid inert materials. All such are inorganic and organic substances. Inorganic substances are z. As sodium chloride, carbonates such as calcium carbonate, bicarbonates, Aluminas, silicas, clays, precipitated or colloidal silica, phosphates.

Organic substances are z. Sugar, cellulose, food and feeds such as milk powder, animal meal, cereal flours and -schrots, strengths.  

Excipients are preservatives, antioxidants, Dyes that have already been listed above are.

Other suitable auxiliaries are lubricants and lubricants such as As magnesium stearate, stearic acid, talc, Bentonites, disintegrating substances such as starch or cross-linked polyvinylpyrrolidone, binders such. B. Starch, gelatin or linear polyvinylpyrrolidone as well Dry binders such as microcrystalline cellulose.

The active ingredients can also be mixed in the preparations with synergists or with other active ingredients available.

Ready-to-use preparations contain the active ingredient in concentrations of 10 ppm-20% by weight, preferably from 0.1-10% by weight.

Preparations that are diluted before use contain the active substance in concentrations of 0.5-90% by weight, preferably from 1 to 50% by weight.

In general, it has proven to be advantageous Amounts from about 0.5 to about 50 mg, preferably 1 to 20 mg, active ingredient per kg of body weight per day to achieve to deliver effective results.

The active ingredients can also be used together with the feed or Drinking water of the animals are administered.  

Feed and food contain 0.01 to 100 ppm, preferably 0.5 to 50 ppm of the active ingredient in combination with a suitable edible material.

Such feed and food can be used both for Healing purposes as well as used for prophylactic purposes become.

The production of such feed and food done by mixing a concentrate or a premix containing 0.5 to 30%, preferably 1 to 20 wt .-% of an active ingredient in admixture with an edible contains organic or inorganic carrier with usual Feed. Edible carriers are z. Cornmeal or corn and soybean meal or mineral salts, the preferably a small amount of edible dust control oil, z. As corn oil or soybean oil. The The premix obtained here can then be the complete Feed before feeding it to the animals be added.

The use in coccidiosis may be mentioned as an example:

For the healing and prophylaxis of coccidiosis, for example Poultry, especially in chickens, ducks, geese and Turkeys are 0.1 to 100 ppm, preferably 0.5 to 100 ppm of an active ingredient with a suitable edible Material, eg. As a nutritious feed, mixed. If desired, these amounts can be increased, especially if the active ingredient is well tolerated by the recipient becomes. Accordingly, administration via the Drinking water done.  

For the treatment of individual animals, z. B. in the case of Treatment of coccidiosis in mammals or the Toxoplasmosis, are preferably drug levels of 0.5 to 100 mg / kg of body weight administered daily to to achieve the desired results. Nevertheless, can It may be necessary at times from the quantities mentioned to deviate, especially as a function of body weight the test animal or the mode of administration, but also because of the animal species and his individual reaction to the active ingredient or the Type of formulation and time or distance, too which he is administered. This is the case in certain cases suffice, with less than the minimum amount mentioned above while in other cases the said upper limit must be exceeded. In the Administration of larger quantities may be appropriate these in the course of the day in several Einzelarreichungen to divide.

The parasites of fish belong to the sub-kingdom the protozoan species of the tribe of Ciliata, z. B. Ichthyophthirius multifiliis, Chilodonella cyprini, Trichodina spp., Glossatella spp., Epistylis spp. of Strain of Myxosporidia, e.g. Myxosoma cerebralis, Myxidium spp., Myxobolus spp., Heneguya spp., Hoferellus spp., the class of Mikrosporidia z. Glugea spp., Thelohania spp., Pleistophora spp., from the trunk of the Plathelminths: trematodes; Monogenea z. B. Dactylogyrus spp., Gyrodactylus spp., Pseudodactylogyrus spp., Diplozoon spp., cestodes, e.g. B. from the groups of  Caryphyllidea (eg Caryophyllaeus laticeps), Pseudophyllidea (eg Diphyllobothrium spp.) and protocephalida (eg. Species of the genus Proteocephalus) and from the stem of Arthropoda various parasitic crustaceans, in particular from the subclasses of Branchiura (fish lice)) and Copepoda (copepods) as well as the orders of the Isopoda (Arseln) and Amphipoda (flea crabs).

The treatment of the fish is either orally, z. B. via the feed or by short-term treatment, "medical Bad ", in which the fish used and in the for a while (minutes to several hours) z. B. kept moving from one breeding tank to another when moving become.

It may also be a temporary or permanent treatment the habitat of the fish (eg whole ponds, Aquariums, tanks or basins) in which the Fish are kept.

The active substance is administered in preparations containing the Applications are adapted.

The concentrations of the active substance are in the preparations at 1 ppm to 10 wt .-%.

Preferred preparations for short-term treatment in the Application as a "medical bath" z. B. in the treatment when moving the fish or treating the fish Habitat (pond treatment) of fish are solutions  the active substance in one or more polar solvents, which react alkaline with dilution with water.

For the preparation of these solutions, the active ingredient in dissolved in a polar, water-soluble solvent, which reacts either alkaline or an alkaline water-soluble substance is added. Latter is advantageously also dissolved in the solvent can but also be suspended in the solvent and be first dissolve in the water. The water should after addition the drug solution has a pH of 7-10, preferably but have a pH of 8-10.

The concentration of the active ingredient may range from 0.5-50%, but preferably within a range of 1-25%.

The solvents are all water-soluble solvents in which the active ingredient is sufficient Concentration is soluble and the physiologically harmless are.

These are ethyl alcohol, isopropyl alcohol, benzyl alcohol, Glycerine, propylene glycol, polyethylene glycols, poly (oxoethylene) - poly (oxypropylene) polymers, basic alcohols such as mono-, di- and triethanolamine, ketones such as acetone or methyl ethyl ketone, esters such as ethyl lactate also N-methylpyrrolidone, dimethylacetamide, dimethylformamide, also dispersing and emulsifying agents such as  polyoxyethylated castor oil, polyethylene glycol sorbitan monooleate, Polyethylene glycol stearate, or polyethylene glycol ether, Polyethylene glycol alkyl amines.

As bases for adjusting the alkaline pH may be mentioned organic bases such as basic amino acids such as L- or D, L-arginine, L- or D, L-lysine, methylglucosamine, Glucosamine, 2-amino-2-hydroxymethylpropanediol (1,3) further as N, N, N ', N'-tetrakis (2-hydroxypropyl) - ethylenediamine or polyether-tetrol on the Based on ethylenediamine (M.G. 480-420), inorganic bases, such as ammonia or sodium carbonate - optionally below Adding water.

The preparations may also contain 0.1 to 20% by weight, preferably 0.1-10% by weight of other formulation auxiliaries, such as antioxidants, surfactants, suspension stabilizers and thickeners such. Methylcellulose, alginates, Polysaccharides, galactomannans and colloidal silicic acid contain. The addition of color, aroma and Builders for animal nutrition is also possible. Also acids, which together with the submitted base Form a buffer system or reduce the pH of the solution, are here to call.

The concentration of the drug depends on the application depending on the type and duration of treatment, as well as age and Condition of the treated fish. It is z. B. at Short term treatment 2-50 mg of active ingredient per liter of water preferably 5-10 mg per liter, at one treatment duration from 3-4 hours. In the treatment of young carp  is z. B. with a concentration of 5-10 mg / l and worked a treatment time of about 1-4 hours.

Eels are about 4 hours with concentrations of about 5 mg / l treated.

For longer treatment duration or for continuous treatment the concentration can be chosen correspondingly lower become.

In pond treatments can be 0.1-5 mg of active ingredient per Liters of water are used.

Preparations for use as feed supplement are z. B. composed as follows:

a) Active ingredient of the formula I. 1-10 parts by weight Soybean protein 49-90 parts by weight b) Active ingredient of the formula I. 0.5-10 parts by weight benzyl alcohol 0.08-1.4 parts by weight hydroxypropyl methylcellulose 0-3.5 parts by weight water Rest ad 100

Preparations for use in "medical baths" and for pond treatment z. B. composed as follows and manufactured.

c) 2.5 g of active ingredient of the formula (I) are dissolved in 100 ml of triethanolamine with heating.
d) 2.5 g of active ingredient of the formula (I)
12.5 g of lactic acid are dissolved in 100 ml of triethanolamine with heating and stirring.
e) 10.0 g of active ingredient of the formula (I) is dissolved in 100 ml of monoethanolamine.

f) Active ingredient of the formula I | 5.0 g propylene glycol 50.0 g sodium 5.0 g water ad 100 ml g) Active ingredient of the formula I. 5.0 g Monoethanolamine 10 g N-methylpyrrolidone ad 100 ml h) active ingredient of the formula I. 2.5 g sodium 5.0 g Polyethylene glycol 200 ad 100 ml

The active ingredient is heated in polyethylene glycol dissolved and sodium carbonate suspended therein.  

example A Coccidiosis in chickens

9 to 11 day old chicks were sporulated with 40 000 Oocysts of highly virulent strains of Eiveria acervulina, E. maxima and E. tenella, den Pathogens of intestinal coccidiosis infected.

3 days before infection and 8 days after infection (End of the experiment) active ingredient was indicated in the Concentration in the food of the animals administered mixed.

The number of oocysts in the faeces was calculated using the McMaster chamber determined (see Engelbrecht and coworkers "Parasitological Working Methods in Medicine and Veterinary Medicine ", p. 172, Akademie-Verlag, Berlin (1965)).

Effective are considered to be those containing the Excretion of oocysts and / or clinical symptoms coccidiosis including mortality completely or to a great extent. In the following table the effective doses are given:  

Table 1

Coccidiosis in chickens

Preparation Examples I Examples of Methods 2a Example 1 2,6-dichloro- α - (4-chlorophenyl) -4- (1-uracil) -phenylacetonitrile

7.45 g (0.018 mol) of 2,6-dichloro- α - (4'-chlorophenyl) -4- (3-ethoxy-acryloyl) ureido-phenylacetonitrile are tert in 150 ml. Butanol dissolved and tert with 2.12 g (0.018 mol) of potassium. Added butylate and heated to boiling for 10 minutes. The solvent is distilled off in vacuo and the residue is heated in vacuo to 100 ° C for 30 minutes. Then it is stirred with water, acidified with acetic acid, the precipitated solid is filtered off and recrystallized from ethanol. As 6.2 g obtained (78% of theory) of 2,6-dichloro- α - (4-chlorophenyl) - 4- (1-uracil) -phenylacetonitrile.

Analog are produced:

example 2 2,6-dichloro-a - (4-trifluoromethylthio) -4- (1-uracil) - phenylacetonitrile example 3 2,6-dichloro- α - (4'-trifluoromethoxy) -4- (1-uracil) - phenylacetonitrile example 4 2,6-dichloro- α - (4-trifluoromethylsulfonyl) -4- (1-uracil) - phenylacetonitrile example 5 2,6-dichloro- α - (2-benzothiazolyl) -4- (1-uracil) - phenylacetonitrile II Examples of Method 2b example 6 2,6-dichloro- α - (2 ', 4'-dichlorophenyl) - α-methyl-4- (3-N-methyl-1-uracil) -phenylacetonitrile

4.5 g (0.01 mol) of 2,6-dichloro- α - (2 ', 4'-dichlorophenyl) - α - methyl-4- (1-uracil) phenylacetonitrile are dissolved in 50 ml of absolute DMSO and mixed with 0.23 g (10 mmol) of NaH added. The mixture is stirred for 20 minutes at room temperature and then 1.85 g (0.013 mol) of methyl iodide in 5 ml of DMSO. The mixture is heated to 50 ° C and kept for 6 hours at this temperature, then concentrated in vacuo and the residue is mixed with water. After filtering off the precipitated solid, 2.64 g (57% of theory) of the N-methyl compound are thus obtained.

Examples of Method 2c example 7 2,6-dichloro- α - (2 ', 6'-dichlorophenyl) -4- (1-uracil) -phenylacetonitrile

5.6 g (0.012 mol) of 2,6-dichloro- α - (2 ', 6'-dichlorophenyl) -4- (5'-carboxy-1'-uracil) -phenylacetonitrile in 10 ml of mercaptoacetic acid at 170 ° C heated. After 1 hour, allowed to cool, mixed with water and after suction of the precipitate is 3.4 g (67% of theory) of 2,6-dichloro- α - (2 ', 6'-dichlorophenyl) -4- (1- uracil) phenylacetonitrile.

example 8 2,6-dichloro- α - (4'-methylphenyl) -4- (1-uracil) -phenylacetonitrile example 9 2,6-dichloro- α - (2'-pyridinyl) -4- (1-uracil) -phenylacetonitrile example 10 2,6-dichloro- α - (4'-trifluoromethylphenyl) -4- (1-uracil) - phenylacetonitrile Examples of Method 4 example 11 2,6-dichloro-a - (4'-chlorophenyl) -4- (N3 ethoxyacryloyl) ureido phenylacetonitrile

10.7 g (0.034 mol) of 2,6-dichloro- α - (4'-chlorophenyl) -4- be aminophenylacetonitrile in 70 ml abs. Toluene dissolved. 150 ml of a prepared from 8.5 g of silver cyanate and 5.6 g Ethoxyacrylsäurechlorid prepared toluene solution and stirred for 1 hour at 40 ° C to drip. The precipitated solid is filtered off with suction, washed with petroleum ether and dried. This gives 12.6 g (82% of theory) of 2,6-dichloro- α - (4'-chlorophenyl) -4- (3-ethoxyacryloyl) ureido phenylacetonitrile.

Analog are produced:

example 12 2,6-dichloro- a - (3 ', 4'-dichlorophenyl) -4-N (3-ethoxyacryloyl) phenylacetonitrile -ureido- example 13 2,6-dichloro- α - (4'-trifluoromethoxyphenyl) -4-N (3-ethoxyacryloyl) -ureido-phenylacetonitrile example 14 2,6-dichloro- α - (4'-trifluoromethylthiophenyl) -4-N (3-ethoxyacryloyl) -ureido-phenylacetonitrile Examples of Method 4b example 15 2,6-dichloro- α - (4'-chlorophenyl) -4-N (3-ethoxyacryloyl) - N'-methylureido-phenylacetonitrile

8.6 g (0.025 mol) of 4-isocyanato-2,6-dichloro- α - (4-chlorophenyl) - a-methyl-phenylacetonitrile are dissolved in absolute tetrahydrofuran. 3.2 g (0.025 mol) of ethoxyacryloyl-N-methylamide are added dropwise thereto and then 600 mg (0.025 mol) of sodium hydride are added in portions. The mixture is heated at 40 ° C. for 1 h and then at 60 ° C. for a further 3 h. After cooling, the precipitated solid is filtered off with suction and crystallized from ethanol. This gives 6.2 g of 2,6-dichloro-α (52% of theory..) - (4'-chlorophenyl) -4-N- (3- ethoxyacryloyl) -N'-methyl-ureido-phenylacetonitrile.

Example of method 6 example 16 2,6-dichloro- α - (4'-methylphenyl) -4- (5-carboxy-1-uracil) - phenylacetonitrile

13.5 g (0.033 mol) of 2,6-dichloro- α - (4'-methylphenyl) -4- (5-carboxy-1-uracil) are phenylacetonitrile 200 ml of HCl / glacial acetic acid (1: 1) was stirred under reflux. It is then mixed with water and filtered off the precipitated carboxylic acid, 8.9 g (63% of theory).

Analog are produced:

example 17 2-chloro-α - (4'-chlorophenyl) -4- (5-carboxy-1-uracil) - phenylacetonitrile example 18 2,6-dichloro- α- phenyl-4- (5-carboxy-1-uracil) phenylacetonitrile example 19 2,6-dichloro- α -4'-methylphenyl-4- (1-uracil) -phenylacetonitrile

12 g (0.03 mol) of cyanuracil are concentrated in 50 ml of HCl. and 30 ml of mercaptoacetic acid stirred for 36 hours under reflux. After cooling, it is diluted with water and filtered off the precipitate. Recrystallization from ethanol yields 7.9 g (70% of theory) 2,6-dichloro-α - (4'-methylphenyl) -4- (1-uracil) -phenylacetonitrile.

Analog are produced:

example 20 2,6-dichloro- α - (2'-chlorophenyl) -4- (1-uracil) -phenylacetonitrile example 21 2,6-dichloro- α - (3'-methylphenyl) -4- (1-uracil) -phenylacetonitrile example 22 2,6-dichloro- a - (2'-fluoro-6'-chlorophenyl) -4- (1-uracil) - phenylacetonitrile Example of method 8 example 23 2,6-dichloro- α - (4'-methylphenyl) -4- (5-cyano-1-uracil) - phenylacetonitrile

17.2 g (0.038 mol) of 2,6-dichloro- α - (4'-methylphenyl) -4- [N- (2- cyanoacryloylurethan] (4.2 g 0.05 mol) of sodium acetate are amino-phenylacetonitrile in 200 ml ethanol is heated for 2 hours under reflux After cooling it is acidified with 2N HCl and filtered off the precipitate so obtained 12.2 g (74% of theory) of 2,6-dichloro- α -.. (4 ' -methylphenyl) -4- (5-cyano-1-uracil) -phenylacetonitrile.

Analog are produced:

example 24 2,6-dichloro- α - (4-chlorophenyl) -4- (5-cyano-1-uracil) - phenylacetonitrile example 25 2,6-dichloro-a - (4-trifluorophenyl) -4- (5-cyano-1-uracil) - phenylacetonitrile Example of Method 10 example 26 2,6-dichloro- α - (4-methylphenyl) -4-N- (2-cyanoacryloylurethan) amino phenylacetonitrile

25 g (0.086 mol) of 2,6-dichloro- α - (4'-methylphenyl) -4-amino-phenylacetonitrile with 17.8 g (0.09 mol) of N- (2-cyano-3-ethoxyacryloyl) urethane stirred in 200 ml of ethanol for 4 hours under reflux. Then concentrated in half and allowed to crystallize the product. This gives 28.2 g (72% of theory) of 2,6-dichloro- α - (4-methylphenyl) -4-N- (2-cyano-acryloylurethan) amino phenylacetonitrile.

Analog are produced:

example 27 2,6-dichloro- α - (4'-chlorophenyl) -4-N- (2-cyanoacryloylurethan) amino phenylacetonitrile example 28 2,6-dichloro- α- methyl- α- phenyl-4-N- (2-cyano-acryloyl-urethane) -amine-phenylacetonitrile

Claims (15)

1. Novel substituted uracils of the general formula (I) in which
R¹ represents aromatic or heteroaromatic radicals which are optionally substituted,
R 2 is H, alkyl, alkenyl, alkynyl or aralkyl which are optionally substituted,
R³ is one or more identical or different radicals of the group hydrogen, halogen, alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, haloalkylthio, cyano, alkoxycarbonyl, alkylsulfonyl, haloalkylsulfonyl,
R⁴ is hydrogen, a straight-chain, branched or cyclic alkyl radical, alkenyl, alkynyl or aralkyl, which are optionally substituted. 2. Process for the preparation of substituted uracils of the general formula (Ia) in which
R¹ represents aromatic or heteroaromatic radicals which are optionally substituted,
R² is hydrogen, alkyl, alkenyl, alkynyl or aralkyl, which are optionally substituted,
R³ is one or more identical or different radicals of the group hydrogen, halogen, alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, haloalkylthio, cyano, alkoxycarbonyl, alkylsulfonyl, haloalkylsulfonyl,
R⁴ is hydrogen, a straight-chain, branched or cyclic alkyl radical, alkenyl, alkynyl or aralkyl, which are optionally substituted,
by

• a) compounds of the formula (II) in which
  R¹, R², R³ and R⁴ have the meanings given above, and
  Alk is C₁-C₄-alkyl, in particular ethyl,
  optionally heated in the presence of bases, or by
• b) Compounds of the formula (Ia) in which R¹, R², R³ and R⁴ have the meanings given above,
  with compounds of the formula (III) R⁴-A in which
  R⁴ is optionally substituted alkyl, alkenyl, alkynyl or aralkyl and
  A represents halogen, -OSO₂-alkyl, -OSO₂-aryl, -OSO₂-haloalkyl,
  or by
• c) Compounds of the formula (IV) in which
  R¹, R², R³ have the meanings given above,
  decarboxylated by heating.

3. Novel compounds of the formula (II) in which
R¹, R², R³ and R⁴ Alk have the meanings given in claim 2. 4. A process for the preparation of the compounds of formula (II) according to claim 3, characterized in that

• a) compounds of the formula (V) in which
  R¹, R², R³ have the abovementioned meanings,
  with isocyanates of the formula (VI) in which
  Alk has the abovementioned meaning,
  implements, or
• b) compounds of the formula (VII) in which R¹, R², R³ have the abovementioned meanings,
  with compounds of the formula (VIII) in which
  R⁴ or Alk has the abovementioned meanings, is reacted.

5. Novel compounds of the formula (IV) in which
R¹, R², R³, R⁴ have the meanings given in claim 1. 6. A process for preparing the novel compounds of the formula (IV) according to 5, characterized in that compounds of the formula (IX) in which
R¹, R², R³, R⁴ have the meanings given in claim 5,
heated in the presence of aqueous acids. 7. Novel compounds of the formula (IX) in which
R¹, R², R³, R⁴ have the meanings given in claim 5. 8. A process for the preparation of the novel compounds of the formula (IX) according to claim 7, which comprises reacting compounds of the formula (X) in which
R¹, R², R³, R⁴, Alk have the meaning given in claim 7,
heated in the presence of bases. 9. Novel compounds of the formula (X) in which
R¹, R², R³, R⁴ and Alk have the meanings described in claim 4b). 10. A process for the preparation of the novel compounds of the formula (X) according to claim 9, which comprises reacting compounds of the formula (V) in which
R¹, R², R³ have the meanings described in claim 4,
with compounds of the formula (XI) in which
Alk is the same or different C₁-C₄-alkyl and R⁴ has the meaning described in claim 4b,
implements. 11. Agents against parasitic protozoa, characterized by a content of at least one substituted Uracil of the formula (I) according to Claim 1. 12. Use of substituted uracils of the formula (I) according to claim 1 for controlling parasitic Protozoa.   13. Method of controlling parasitic protozoa, characterized in that substituted Uracile of formula (I) according to claim 1 on this and / or their habitat. 14. Process for the preparation of agents against parasitic Protozoa, characterized in that substituted uracils of the formula (I) according to claim 1 with extenders and / or surface-active Mixtures mixed. 15. Use of substituted uracils of the formula (I) according to claim 1 for the preparation of agents against parasitic protozoa.